We examined the association of TNF-related apoptosis-inducing ligand (TRAIL) concentrations with cardiovascular disease (CVD) in rheumatoid arthritis (RA) and, since osteoprotegerin (OPG) can act as a decoy receptor for TRAIL, whether TRAIL concentrations impact on the OPG level-atherosclerotic CVD relation that was recently documented in the present cohort.TRAIL concentrations were assessed by ELISA in 151 RA patients of which 75 (49.7%) had CVD comprising ischaemic heart disease (n=27), cerebrovascular accident (n=26), peripheral artery disease (n=9) or/and heart failure (HF) (n=27), and 62 controls.Mean RA duration was 12 years. In RA patients, C-reactive protein (CRP) levels and cholesterol-HDL cholesterol ratio related to TRAIL concentrations [partial R=-0.222 (p=0.006) and 0.174 (p=0.04), respectively]. TRAIL concentrations were smaller in RA patients compared to controls (median (interquartile range) = 80.2 (60.9-120.4) versus 130.4 (89.4-167.7) pg/ml, p<0.0001)). TRAIL levels were larger in RA patients with compared to those without HF (105.5 (66.5-143.4) versus 79.9 (57.8-110.6), p=0.02); this difference was independent of demographic characteristics and traditional cardiovascular risk factors (p=0.04) but not CRP concentrations (p=0.1). TRAIL levels were consistently unrelated to atherosclerotic CVD. Our previously reported OPG-atherosclerotic CVD relation in RA survived adjustment for TRAIL concentrations in a mixed regression model (p=0.04).TRAIL concentrations are markedly reduced and associated with HF in established RA, this relationship being explained by CRP levels. OPG may directly enhance CVD risk in RA.